WO2019086008A1 - Forme cristalline de dérivé de benzotriazole et procédé de préparation et utilisation associés - Google Patents

Forme cristalline de dérivé de benzotriazole et procédé de préparation et utilisation associés Download PDF

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WO2019086008A1
WO2019086008A1 PCT/CN2018/113806 CN2018113806W WO2019086008A1 WO 2019086008 A1 WO2019086008 A1 WO 2019086008A1 CN 2018113806 W CN2018113806 W CN 2018113806W WO 2019086008 A1 WO2019086008 A1 WO 2019086008A1
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compound
formula
solvent
reaction
group
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PCT/CN2018/113806
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Chinese (zh)
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邱关鹏
张晨
魏用刚
卢泳华
祝国智
高秋
楚洪柱
李瑶
严庞科
郑伟
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四川海思科制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a crystalline form of a benzotriazole derivative, a process for its preparation and its use in medicine.
  • Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • Bronchodilators in clinical use include widely muscarinic receptor antagonist and ⁇ 2 - adrenergic agonist.
  • a muscarinic receptor antagonist exerts potency in bronchodilation by reducing the level of vagal cholinergic energy in airway smooth muscle.
  • 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine.
  • drugs with dual effects of muscarinic receptor antagonism and ⁇ 2 -adrenergic agonism are currently in clinical trials.
  • This bifunctional drug has the pharmaceutical advantages of a combination of two components, and has a single molecular drug. Generation dynamics. These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action.
  • compounds with muscarinic receptor antagonism and ⁇ 2 -adrenergic agonistic dual action can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple The therapeutic effect of the effect.
  • ICS corticosteroid
  • the present invention provides a crystalline form of a benzotriazole derivative having a dual action of muscarinic receptor antagonism and ⁇ 2 -adrenergic agonism, a preparation method thereof and use thereof in medicine.
  • the crystallization of the compound of the formula (I) of the present invention has the following advantages such as ease of processing and crystallization, convenient handling, ease of purification, ease of industrialization, good stability, good fluidity, easy micronization, etc., which make them particularly suitable for Made into an inhalation preparation.
  • the present invention provides a crystal of a compound of the formula (I), which has a characteristic diffraction peak at the following 2 ⁇ position using Cu-K ⁇ radiation: 6.03° ⁇ 0.2°, 9.11° ⁇ 0.2°, 10.68 ° ⁇ 0.2°, 11.16° ⁇ 0.2°, 11.78° ⁇ 0.2°, 13.52° ⁇ 0.2°, 15.04° ⁇ 0.2°, 16.05° ⁇ 0.2°, 16.86° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.91° ⁇ 0.2°, 19.08° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.24° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.47° ⁇ 0.2°, 24.36° ⁇ 0.2°, 27.36° ⁇ 0.2°;
  • the crystallization of the compound of formula (I) uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.03° ⁇ 0.2°, 7.59° ⁇ 0.2 °, 9.11 ° ⁇ 0.2 °, 10.68 ° ⁇ 0.2 °, 11.16 ° ⁇ 0.2 °, 11.78 ° ⁇ 0.2 °, 12.64 ° ⁇ 0.2 °, 13.52 ° ⁇ 0.2 °, 15.04 ° ⁇ 0.2 °, 16.05 ° ⁇ 0.2 °, 16.86° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.91° ⁇ 0.2°, 19.08° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.21° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.24° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.47° ⁇ 0.2°, 24.36° ⁇ 0.2°, 25.55° ⁇ 0.2°
  • the crystallization of the compound of formula (I) uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.03° ⁇ 0.2°, 7.59° ⁇ 0.2 °, 9.11 ° ⁇ 0.2 °, 10.68 ° ⁇ 0.2 °, 11.16 ° ⁇ 0.2 °, 11.78 ° ⁇ 0.2 °, 12.64 ° ⁇ 0.2 °, 13.52 ° ⁇ 0.2 °, 15.04 ° ⁇ 0.2 °, 16.05 ° ⁇ 0.2 °, 16.86° ⁇ 0.2°, 17.40° ⁇ 0.2°, 17.91° ⁇ 0.2°, 19.08° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.21° ⁇ 0.2°, 20.48° ⁇ 0.2°, 21.24° ⁇ 0.2°, 22.03° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.47° ⁇ 0.2°, 24.36° ⁇ 0.2°, 25.04° ⁇ 0.2°
  • X-ray powder diffraction pattern of the compound of the formula (I) is substantially as shown in Fig. 1.
  • DSC differential scanning calorimetry curve
  • DSC differential scanning calorimetry curve
  • the melting peak height of the DSC curve depends on a number of factors associated with sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details.
  • the crystalline compound of the present invention is characterized by a DSC pattern having a characteristic peak position having substantially the same properties as the DSC pattern provided in the drawings of the present invention with a margin of error of ⁇ 3 °C.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound crystal of the above formula (I), and a pharmaceutically acceptable carrier or excipient; preferably, the composition is formulated for inhalation administration Form; preferably, the inhaled administration form is selected from a dry powder inhalation formulation or an aerosol.
  • the present invention also provides the use of the compound crystal of the above formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for preventing and/or treating an airway obstructive disease; preferably, asthma, chronic obstructiveness Pulmonary disease or bronchitis.
  • an airway obstructive disease preferably, asthma, chronic obstructiveness Pulmonary disease or bronchitis.
  • the present invention also provides a method for treating an airway obstructive disease, which comprises administering a compound crystal of any one of the above formula (I) or a pharmaceutical composition thereof, wherein the airway obstructive disease is preferably asthma, chronic obstruction Sexual lung disease or bronchitis.
  • the present invention relates to a process for the preparation of a crystal of a compound of the formula (I), which comprises recrystallizing and/or beating a compound of the formula (I) in a solvent selected from the group consisting of C 6-10 aromatic hydrocarbon solvents , C 5-10 alkane solvent, C 1-6 halogenated alkane solvent, C 1-6 alcohol solvent, C 2-6 ester solvent, C 2-6 ether solvent, C 1-6 ketone solvent and One or more of the water; preferably the solvent is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, One or more of isopropyl acetate, acetone, diethyl ether, methyl tert-butyl ether, and water; preferably seed crystals are added upon recrystallization.
  • a solvent selected from
  • the solvent for recrystallization and/or beating is selected from the group consisting of toluene, n-heptane, n-hexane, methanol, ethanol, isopropanol, dichloromethane.
  • the present invention relates to an embodiment of the process for producing a crystal of the compound of the formula (I), wherein the temperature for recrystallization and/or beating is from 0 ° C to reflux; preferably from 0 to 80 ° C; more preferably from 20 to 60 ° C; further preferably 20 ⁇ 40 ° C.
  • the present invention relates to an embodiment of the preparation method of the crystal of the compound represented by the formula (I), wherein the solvent is selected from the group consisting of a mixed solvent of dichloromethane and isopropanol; and the volume ratio thereof is preferably 5:1 to 1:5; It is preferably 2:1 to 1:2; further preferably 1:1; the temperature for recrystallization and/or beating is preferably 20 to 60 ° C; more preferably 20 to 40 ° C.
  • the solvent is selected from the group consisting of a mixed solvent of dichloromethane and isopropanol; and the volume ratio thereof is preferably 5:1 to 1:5; It is preferably 2:1 to 1:2; further preferably 1:1; the temperature for recrystallization and/or beating is preferably 20 to 60 ° C; more preferably 20 to 40 ° C.
  • the present invention provides a method for preparing a compound represented by the formula (I),
  • a desilicon ether reagent preferably tetrabutylammonium fluoride or a hydrate thereof, triethylamine Trihydrofluoride or pyridine hydrofluoride.
  • the present invention relates to an embodiment of the process for the preparation of the compound of the formula (I), wherein the desilicon ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridinium hydrogen Fluorate.
  • the desilicon ether reagent is selected from the group consisting of tetrabutylammonium fluoride or a hydrate thereof, triethylamine trihydrofluoride or pyridinium hydrogen Fluorate.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (I), wherein the C 1-6 alcohol solvent is one or more selected from the group consisting of methanol, ethanol and isopropanol; and the reaction temperature is preferably 0 to 60. °C; more preferably 20 to 60 ° C; more preferably 20 to 50 ° C.
  • the silyl ether reagent is preferably triethylamine trihydrofluoride; the temperature of the reaction is preferably 0 to 60 ° C; more preferably 20 to 60 ° C; more preferably 20 to 50 ° C.
  • the invention also relates to a method for preparing a compound represented by the formula (II),
  • the compound of the formula (III) and the compound of the formula (VI) are carried out in the presence of a reducing agent;
  • HA is selected from organic or inorganic acids; preferably HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • the reducing agent is selected from the group consisting of organoboron reducing agents; preferably sodium tris(acetoxy)borohydride, sodium borohydride, sodium cyanoborohydride or hydrazine Borane.
  • the solvent of the reaction is selected from the group consisting of polar solvents; preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2- Methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetamide, N,N-dimethylacetamide, N,N-dimethylformamide And one or more of dimethyl sulfoxide; the temperature of the reaction is preferably 0 to 60 ° C;
  • the reaction is optionally carried out in the presence of a molecular sieve, a dehydrating agent or a water separation vessel;
  • the dehydrating agent is preferably a molecular sieve, sodium sulfate or magnesium sulfate;
  • the reaction is optionally carried out in the presence of an acidic catalyst; preferably the acid catalyst is one or more of formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and zinc chloride. .
  • the acid catalyst is one or more of formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and zinc chloride.
  • the present invention relates to a method for preparing the compound of the formula (II), the molar ratio of the reducing agent to the compound of the formula (III) is 1:1 to 1:3; preferably 1:1 to 1:2;
  • the reducing agent is preferably sodium tris(acetoxy)borohydride;
  • the temperature of the reaction is preferably 0 to 60 ° C; more preferably 0 to 40 ° C;
  • the reaction optionally in the molecular sieve and acetic acid is carried out in the presence.
  • reaction is carried out in the presence of a metal catalyst and triethylsilane;
  • HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (IV), wherein the solvent in the reaction is selected from a C 1-6 alcohol solvent; preferably methanol or ethanol;
  • the metal catalyst is selected from the group consisting of palladium black, palladium/carbon, palladium hydroxide/carbon, palladium chloride/carbon, Raney nickel, platinum/carbon or platinum oxide;
  • the temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 0 to 40 ° C;
  • the present invention relates to an embodiment of the preparation method of the compound of the formula (IV). After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated to obtain a concentrate. The concentrate is dissolved in an organic solvent, and HA is added to form a formula (IV).
  • the organic solvent is preferably a polar solvent; preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl uncle
  • a polar solvent preferably dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl uncle
  • butyl ether, methanol, ethanol, isopropanol acetamide, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethyl sulfoxide.
  • the mass ratio of the metal catalyst (preferably palladium/carbon) to the compound of the formula (IV) is preferably from 1:1 to 1:100; more preferably 1:1 to 1:10; more preferably 1:1 to 1:5;
  • the molar ratio of triethylsilane to the compound of the formula (IV) is preferably from 20:1 to 1:1; more preferably from 10:1 to 1:1; more preferably from 5:1 to 1:1;
  • the temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 0 ° C to 40 ° C.
  • the compound of formula (IV) is purified by recrystallization; the solvent for recrystallization is preferably 2-methyltetrahydrofuran or/and tetrahydrofuran.
  • the product obtained after recrystallization has high purity, simple purification and easy industrialization.
  • the present invention relates to a process for the preparation of a compound of formula (V),
  • the compound of the formula (VI) is reacted in the presence of an alkaline reagent.
  • the present invention relates to an embodiment of the preparation method of the compound represented by the formula (V), wherein the alkaline agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium acetate, potassium fluoride, cesium fluoride, One or more of cesium carbonate, potassium carbonate, potassium acetate, and 1,8-diazabicycloundec-7-ene;
  • the alkaline agent is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium acetate, potassium fluoride, cesium fluoride, One or more of cesium carbonate, potassium carbonate, potassium acetate, and 1,8-diazabicycloundec-7-ene;
  • the solvent to be reacted is selected from the group consisting of a C 1-6 halogenated alkane solvent, a C 1-6 alcohol solvent, a C 2-6 ester solvent, a C 2-6 ether solvent, a C 1-6 ketone solvent, N, N- One or more of dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and water; preferably dichloromethane, chloroform, 1,2-dichloromethane, methanol, ethanol, iso Propyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetone, N,N-dimethylformamide, N,N-dimethylacetamide And one or more of the water;
  • the temperature of the reaction is preferably from 0 ° C to reflux; more preferably from 20 ° C to 80 ° C.
  • the invention provides a preparation method of the compound represented by the formula (I), which comprises the following steps:
  • HA is selected from the group consisting of HF, HBr, HCl, CH 3 COOH, benzenesulfonic acid or p-toluenesulfonic acid.
  • a compound of the formula (VI) is formed in the presence of an alkaline reagent to form a compound of the formula (V), and the solvent to be reacted is selected from the group consisting of a mixture of N,N-dimethylformamide and one or two of water.
  • the alkaline agent is selected from lithium hydroxide; the temperature of the reaction is preferably from 20 ° C to 80 ° C;
  • the solvent of the reaction is selected from ethanol; the reaction temperature is preferably 0 ⁇ 40 ° C;
  • a compound of the formula (IV) is reacted with a compound of the formula (III) in the presence of sodium tris(acetoxy)borohydride to form a compound of the formula (II), and the solvent of the reaction is selected from the group consisting of dimethyl a mixture of one or more of sulfone, dichloromethane, isopropanol, acetonitrile and acetamide.
  • the solvent of the reaction is selected from the group consisting of dimethyl a mixture of one or more of sulfone, dichloromethane, isopropanol, acetonitrile and acetamide.
  • a molecular sieve is added to the reaction.
  • one or two of acetic acid and zinc chloride are added to the reaction. Mixing; the temperature of the reaction is preferably 0 to 40 ° C;
  • the solvent of the reaction is selected from ethanol; the reaction temperature is preferably 0 to 60 ° C;
  • the present invention provides a compound of the formula (IV):
  • HA is selected from HF, HBr, HCl, methanesulfonic acid or p-toluenesulfonic acid.
  • Figure 1 X-ray powder diffraction pattern of Compound 1 crystals.
  • Figure 2 Differential scanning calorimetry curve of compound 1 crystals.
  • Figure 3 Amorphous X-ray powder diffraction pattern of Compound 1.
  • Figure 4 X-ray powder diffraction pattern of Compound 1 seed crystals.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the solution means an aqueous solution.
  • the room temperature is 20 ° C to 30 ° C.
  • 1D (70 g, 176 mmol) was added to 250 mL of DMSO and 200 mL of isopropanol
  • 1E (70 g, 117 mmol, synthesized with reference to WO2017012489A1), 4A molecular sieve 70 g, and acetic acid (3.5 g, 58.5 mmol) were added with stirring, and stirred for 2 hours after the addition.
  • Sodium triacetoxyborohydride (70 g, 330 mmol) was added portionwise, and stirred at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was poured into 3 kg of ice water, extracted with 2 L of dichloromethane, and extracted with 1 L of dichloromethane.
  • Step 5 [7-[3-[5-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)) Ethyl]amino]methyl]benzotriazol-1-yl]propyl]-7-azaspiro[3.5]non-2-yl]2-hydroxy-2,2-bis(2-thienyl) Acetate (compound 1)
  • the compound 1 obtained by this method was subjected to a PXRD test, and the drawing is shown in Fig. 3.
  • the test methods and conditions were in agreement with the crystal of Compound 1 in Example 2.
  • Compound 1 obtained at this time was amorphous.
  • Method 2 Weigh about 15 mg of Compound 1 (prepared from Example 1) in a 3 ml vial, add 0.5 ml of isopropanol, magnetically stir at 500 ° C for 2 h at 50 ° C, and filter with a 0.45 ⁇ m PTFE filter. The supernatant. The obtained supernatant was cooled from 50 ° C to 5 ° C at a rate of 0.1 ° C / min and kept at a constant temperature of 5 ° C, and the precipitated solid was collected, which was a seed crystal of Compound 1.
  • Method 3 Weigh 1.0 g of Compound 1 (prepared from Example 1) in a 10 ml single-mouth bottle, add 1:1 (v/v) dichloromethane: isopropanol (1.8 mL), and warm to 40 ° C. The raw material was not completely dissolved. The mixture was stirred at this temperature for 8 hours, then allowed to stand for 3 days, the solution became cloudy, 3 ml of dichloromethane was added, stirred, filtered, and the filter cake was washed with 1 ml of dichloromethane to obtain a solid 1: light red. Solid 10 mg.
  • the filter cake was dried under vacuum at 50 ° C for 1 hour, then pulverized into a powder, and dried under vacuum at 70 ° C for 40 hours to give a crystalline compound 1 as a white solid (36 g, yield 53.7%, HPLC: 99.3%).
  • the crystal of Compound 1 and the seed crystal of Compound 1 were subjected to X-ray powder diffraction test as follows.
  • the crystal of Compound 1 was subjected to differential scanning calorimetry analysis as follows.
  • DSC Differential Scanning Calorimetry testing was performed using the NETZSCH DSC 214 Polyma. About 1 mg of the sample was weighed into a pinhole-coated aluminum crucible, and nitrogen gas was used as a purge gas (flow rate: 60 ml/min), and the initial temperature was 35 ° C, and the temperature was raised to 200 ° C at a temperature increase rate of 10 ° C / min.
  • the DSC differential scanning calorimetry curve of the crystal of Compound 1 is shown in Figure 2.

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Abstract

La présente invention concerne une forme cristalline d'un composé représenté par la formule (I) et un procédé de préparation et une utilisation médicale associés. (I)
PCT/CN2018/113806 2017-11-02 2018-11-02 Forme cristalline de dérivé de benzotriazole et procédé de préparation et utilisation associés WO2019086008A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017012489A1 (fr) * 2015-07-21 2017-01-26 四川海思科制药有限公司 Dérivé de cycle benzène à activités agonistique du récepteur β2 et antagonistique du récepteur m3, et utilisation médicale de celui-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017012489A1 (fr) * 2015-07-21 2017-01-26 四川海思科制药有限公司 Dérivé de cycle benzène à activités agonistique du récepteur β2 et antagonistique du récepteur m3, et utilisation médicale de celui-ci

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